title: Nuclear but not cytosolic phosphoinositide 3-kinase beta has an essential function in cell survival.
abstract: Class I(A) phosphoinositide 3-kinases (PI3Ks) are heterodimeric enzymes composed of a p85 regulatory and a p110 catalytic subunit that induce the formation of 3-polyphosphoinositides, which mediate cell survival, division, and migration. There are two ubiquitous PI3K isoforms p110α and p110β that have nonredundant functions in embryonic development and cell division. However, whereas p110α concentrates in the cytoplasm, p110β localizes to the nucleus and modulates nuclear processes such as DNA replication and repair. At present, the structural features that determine p110β nuclear localization remain unknown. We describe here that association with the p85β regulatory subunit controls p110β nuclear localization. We identified a nuclear localization signal (NLS) in p110β C2 domain that mediates its nuclear entry, as well as a nuclear export sequence (NES) in p85β. Deletion of p110β induced apoptosis, and complementation with the cytoplasmic C2-NLS p110β mutant was unable to restore cell survival. These studies show that p110β NLS and p85β NES regulate p85β/p110β nuclear localization, supporting the idea that nuclear, but not cytoplasmic, p110β controls cell survival.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Campus de Cantoblanco, Madrid E-28049, Spain.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Javier
authors.initials: J
authors.lastname: Redondo-Muñoz
authors.forename: Vicente
authors.initials: V
authors.lastname: Perez-García
authors.forename: Isabel
authors.initials: I
authors.lastname: Cortes
authors.forename: Monica
authors.initials: M
authors.lastname: Chagoyen
authors.forename: Ana C
authors.initials: AC
authors.lastname: Carrera
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology*; D002470:Cell Survival; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; C497132:PIK3CB protein, human; C546640:Pik3cb protein, mouse